Provocative pattern of rearrangements of the genes for the γ and β chains of the T-cell receptor in human leukemias

To examine the distribution of rearrangements of the γ- and β-chain T-cell receptor (TCR) genes in T- and non-T acute lymphoblastic leukemias (ALLs), and potentially to determine which genes rearrange first in ontogeny, we analyzed high molecular weight DNA from 102 patients with acute leukemia. Rearranged γ- and β-chain genes were found in all T-cell ALLs (22/22) examined. Overall, 27% (18/66) of B-lineage ALLs and β-chain gene rearrangements, and 41% (24/58) had γ-chain gene rearrangements, but the distribution of rearranged genes varied according to the stage of B-cell differentiation. The γ-chain genes were rearranged in 11% (1/9) of the B-lineage patients negative for the common acute lymphoblastic leukemia antigen (cALLA) and 50% (23/46) of cALLA⁺ ALL patients, while the β-chain genes were not rearranged in any of the 7 cALLA^- ALL patients examined but were rearranged in 32% (18/56) of the cALLA⁺ patients. Neither TCR gene was found to be rearranged in acute nonlymphoid leukemia patients (0/12) or in patients with B-cell (surface immunoglobulin-positive) leukemia (0/3). Of the 44 cALLA⁺ patients in which a direct comparison of γ- and β-chain gene rearrangements could be made, 34% had both genes rearranged, 16% had only γ-chain gene rearrangements, and the remaining 50% had both genes in the germ-line configuration. β-Chain rearrangements have not been found in the absence of γ-chain rearrangements, thus supporting a proposed hierarchy of TCR gene rearrangements. A provocative finding was that only a small percentage (11%) of the patients with cALLA^- B percursor cell ALLs had rearranged TCR genes, while 50% of the cALLA⁺ leukemia patients had at least γ-chain rearrangement, raising a question as to whether indeed cALLA^- cells are precursors to cALLA⁺ cells. Interestingly, 18% (2/11) of the cytoplasmic immunoglobulin (cIg)-positive cALLA⁺ (pre-B) ALLs involved TCR gene rearrangements, compared to 60% (21/35) of the cIg-negative cases, suggesting the possibility that the majority of functional B cells are derived from the cALLA⁺ pool that contains immunoglobulin but not TCR gene rearrangements.